Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and seven hundred thousand children die from the infection in 2012. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of the parasite provides one approach to new drug development. Plasmodium falciparum causes the most virulent form of human malaria. A striking feature of P. falciparum- erythrocytic infection is that hundreds of parasite proteins are exported to the host cell. The export mechanism is mediated by an N terminal host-targeting signal on parasite proteins that binds to the lipid phosphatidylinositol-3-phosphate [PI(3)P] within the parasite's endoplasmic reticulum (ER). Unlike organelles of yeast and mammalian cells, destinations in the red cell lie beyond the plasma membrane of the parasite. Moreover, the red cell has no endogenous transport structures or machinery. The long term aim of this proposal is to understand and characterize how the erythrocyte is accessed by the intracellular parasite and the identification critical parasite mechanisms that enable exit fro the parasite's ER. Molecular, genetic, genomic tools, bioinformatics, high resolution imaging techniques, biochemical subcellular fractionation assays, biophysical measurements of lipid-protein interactions, membrane bending and penetration will be used in analysis, as will transgenic reporters, endogenous parasite proteins, drugs and drug resistant parasites. The consequence of drugs on lipid-protein interactions in the ER, variant antigen expression on the erythrocyte surface and parasite killing will be evaluated. These studies are needed to understand basic mechanisms of malaria parasite biology, erythrocyte remodeling and malarial virulence. They will open up new targets for anti-malarial therapy, and thereby contribute to human health.